title: Breakdown of T cell tolerance and autoimmunity in primary immunodeficiency--lessons learned from monogenic disorders in mice and men.
abstract: A key feature of the immune system is the capacity to monitor and control infections from non-self pathogens while maintaining tolerance to self-antigens. Primary immunodeficiencies (PID) are characterized by an increased susceptibility to infections, often associated with aberrant inflammatory responses and a concomitant high prevalence of autoimmunity. Autoimmunity in PID raises a conundrum: How can an immune system fail to respond to non-self pathogens while reacting vigorously to self-antigens? Recent advances from studies of PID patients and related animal models have revealed the crucial role of Aire-induced expression of self-antigens for deletion of autoreactive T cells in the thymus (central tolerance). Moreover, lessons from PID have provided unequivocal evidence for the essential role of regulatory T cells in suppressing autoreactive T cells in the periphery. Finally, findings from PID have broadened our understanding of how homeostatic proliferation and increased load or decreased clearance of apoptotic cells and non-self pathogens can lead to breakdown of peripheral tolerance.
authors.affiliation: Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Westerberg
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D017637:Clonal Deletion / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology* / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism; D000096927:AIRE Protein
chemical_list: D001324:Autoantigens; D014157:Transcription Factors; D000096927:AIRE Protein